Mise Masashi, Yadera Seiji, Matsuda Michiaki, Hashizume Takanori, Matsumoto Satoshi, Terauchi Yoshiaki, Fujii Toshihiko
Pharmacokinetics and Physico-Chemical Property Research Laboratories, Dainippon Pharmaceutical Co, Ltd, Osaka 564-0053, Japan.
Drug Metab Dispos. 2004 Feb;32(2):240-5. doi: 10.1124/dmd.32.2.240.
5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine (AC-3933) is a novel cognitive enhancer with central benzodiazepine receptor partial inverse agonistic activity. AC-3933 is predominantly metabolized to hydroxylated metabolite [SX-5745; 3-(5-hydroxymethyl-1,2,4-oxadiazol-3-yl)-5-(3-methoxyphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridine] in dog. Initially, we found that there is considerable interindividual variability in AC-3933 hydroxylation in dogs and that dogs could be phenotyped as extensive metabolizer (EM) and poor metabolizer (PM). Then, to clarify the cause of AC-3933 polymorphic hydroxylation in dogs, in vitro studies were carried out using liver microsomes from EM and PM dogs. Our results show that AC-3933 hydroxylation clearance in PM dogs was much lower than that in EM dogs (0.2 versus 10.8-20.5 microl/min/mg, respectively). In addition, AC-3933 hydroxylation was significantly inhibited by alpha-naphthoflavone, a CYP1A inhibitor, and by anti-CYP1A2 antibodies, indicating that CYP1A2 was responsible for the polymorphic hydroxylation of AC-3933 in dogs. Furthermore, immunoblotting results have shown that although CYP1A2 protein was not detected in PM dogs (<0.86 pmol/mg), CYP1A2 content in EM dogs was prominent (6.1-13.0 pmol/mg). These results indicate that AC-3933 polymorphic hydroxylation arises from the polymorphic expression of CYP1A2 in dogs, which might involve genetic polymorphism of the CYP1A2 gene.
5-(3-甲氧基苯基)-3-(5-甲基-1,2,4-恶二唑-3-基)-2-氧代-1,2-二氢-1,6-萘啶(AC-3933)是一种具有中枢苯二氮䓬受体部分反向激动活性的新型认知增强剂。在犬体内，AC-3933主要代谢为羟基化代谢物[SX-5745；3-(5-羟甲基-1,2,4-恶二唑-3-基)-5-(3-甲氧基苯基)-2-氧代-1,2-二氢-1,6-萘啶]。最初，我们发现犬体内AC-3933羟基化存在显著的个体间差异，并且犬可分为快代谢型(EM)和慢代谢型(PM)。然后，为了阐明犬体内AC-3933多态性羟基化的原因，使用EM犬和PM犬的肝微粒体进行了体外研究。我们的结果表明，PM犬体内AC-3933的羟基化清除率远低于EM犬(分别为0.2与10.8 - 20.5微升/分钟/毫克)。此外，AC-3933的羟基化受到CYP1A抑制剂α-萘黄酮和抗CYP1A2抗体的显著抑制，表明CYP1A2是犬体内AC-3933多态性羟基化的原因。此外，免疫印迹结果显示，虽然在PM犬中未检测到CYP1A2蛋白(<0.86皮摩尔/毫克)，但EM犬中CYP1A2含量显著(6.1 - 13.0皮摩尔/毫克)。这些结果表明，犬体内AC-3933的多态性羟基化源于CYP1A2的多态性表达，这可能涉及CYP1A2基因的遗传多态性。
